Cpg Aih Final

EASL Clinical Practice Guidelines: Autoimmune hepatitisq

European Association for the Study of the Liver

Introduction

Autoimmune hepatitis (AIH) was the rst liver disease for whichan effective therapeutic intervention, corticosteroid treatment,was convincingly demonstrated in controlled clinical trials.However, 50 years later AIH still remains a major diagnosticand therapeutic challenge. There are two major reasons for thisapparent contradiction: Firstly, AIH is a relatively rare disease.Secondly, AIH is a very heterogeneous disease.

Like other rare diseases, clinical studies are hampered by thelimited number of patients that can be included in trials. Possiblyand more importantly, the interest of the pharmaceutical indus-try to develop effective specic therapies for rare diseases is lim-ited due to the very restricted market for such products. The wideheterogeneity of affected patients and clinical manifestations ofthe disease limits both diagnostic and further therapeutic studies.AIHs age spectrum is extremely wide, it can affect small infantsand can manifest for the rst time in octogenarians. AIH can run avery mild subclinical course or be very acute, rarely leading tofulminant hepatic failure. AIH sometimes demonstrates quitedramatic disease uctuations with periods of apparent sponta-neous remissions, acute ares and/or smouldering disease. AIHcan be associated with a number of other hepatic conditions, inparticular the cholestatic liver diseases; primary biliary cirrhosis(PBC) or primary sclerosing cholangitis (PSC), but also withdrug-induced liver injury (DILI), alcoholic or non-alcoholicsteatohepatitis (NASH) or viral hepatitis. Each condition providesspecial diagnostic and therapeutic challenges. Despite these chal-lenges and complexities, diagnosis and treatment of AIH has seen

striking progress, and now patients in specialised centres have anexcellent prognosis, both in respect to survival and to quality oflife.

The aim of the present Clinical Practice Guideline (CPG) is toprovide guidance to hepatologists and general physicians in thediagnosis and treatment of AIH in order to improve care foraffected patients. In view of the limited data from large con-trolled studies and trials, many recommendations are based onexpert consensus. This is to some extent a limitation of thisEASL-CPG, but at the same time it is its special strength: consen-sus in this guideline is based on intensive discussions of expertsfrom large treatment centres. The core consensus group hasexperience of over one thousand AIH patients managed person-ally, and the recommendations have been reviewed by both theEASL Governing Board as well as external experts, who have asimilarly wide personal experience. Therefore, the guidelinesare a resource of information and recommendations based onthe largest experience available thus far. At the same time, weformulate key scientic questions that result from the consensusdiscussions on the limitations of our knowledge. All recommen-dations of this CPG were agreed upon unanimously (100%) con-sensus. Grading of the recommendations is based on theGRADE system for evidence (Table 1) [1].

Epidemiology of AIH

AIH is an non-resolving chronic liver disease that affects mainlywomen and is characterized by hypergammaglobulinaemia evenin the absence of cirrhosis, circulating autoantibodies, associationwith human leukocyte antigens (HLA) DR3 or DR4, interface hep-atitis on liver histology, and a favourable response to immuno-suppression [25]. The disease, if untreated, often leads tocirrhosis, liver failure and death.

AIH is considered relatively rare, as its prevalence ranges from16 to 18 cases per 100,000 inhabitants in Europe [611]. Untilrecently, the incidence and prevalence of AIH on a population-based level was assessed in only two studies [6,9]. Interestinglyhowever, higher prevalence rates have been reported in areaswith quite stable populations. For instance, prevalence rates of42.9 cases per 100,000 and 24.5 cases per 100,000 inhabitantshave been reported in Alaska natives [12] and New Zealand [9],respectively. In addition, a large Danish nationwide population-based study assessed the incidence and prevalence of AIH inDenmark during a nearly 20 year time period ranging from1994 to 2012 including 1721 AIH patients [13]. The most strikingobservation in that study was the marked increase in AIH inci-dence over time, which could not be attributed to a relative

Journal of Hepatology 2015 vol. 63 j 9711004

Received 30 June 2015; accepted 30 June 2015Chairman: Ansgar W. Lohse.Panel members: Olivier Chazouillres, George Dalekos, Joost Drenth, MichaelHeneghan, Harald Hofer, Frank Lammert, Marco Lenzi. Correspondence: EASL ofce, 7 Rue Daubin, CH 1203 Geneva, Switzerland.Tel.: +41 22 807 0360; fax: +41 22 328 0724.E-mail address: [email protected]: ACG, American College of Gastroenterology; AGA, AmericanGastroenterological Association; ANCA, Antineutrophil cytoplasmic antibodies;APECED, Autoimmune polyendocrinopathy-cadidiasis ectodermal dystrophy; AS,acute severe autoimmune; CNI, Calcineurin inhibitor; CPG, Clinical PracticeGuideline; DEXA, Dual energy x-ray absorptiometry; DILI, Drug-induced liverinjury; HAI, Hepatitis activity index; HBV, Hepatitis B virus; HLA, Humanleukocyte antigens; HRQoL, Health related quality of life; IBD, Inammatorybowel disease; IgG, Immunoglobulin G; LBR, Live birth rate; LT, Livertransplantation; MMF, Mycophenolate mofetil; MRCP, Magnetic resonancecholangiopancreatography; NAFLD, Non-alcoholic fatty liver disease; NASH,Non-alcoholic steatohepatitis; PBC, Primary biliary cirrhosis; PROM, Patientreported Outcome Measures; PSC, Primary sclerosing cholangitis; SCBU, Specialcare baby unit; SMA, Smooth muscle antibodies; TPMT, Thiopurinemethyltransferase.

Clinical Practice Guidelines

change in case ascertainment rates. Actually, the incidence rate ofAIH in Denmark has nearly doubled between 1994 to 2012,reaching a point prevalence in 2012 of 24/100,000 (35/100,000for females) [13].

AIH prevalence and clinical expression seem to vary accordingto ethnicity. Alaskan natives appear to have a high frequency ofacute icteric disease at the disease onset [12], and the diseaseis more common and more severe in North AmericanAboriginal/First Nations populations compared with predomi-nantly Caucasian, non-First Nations populations [14]. African-American patients more commonly have cirrhosis, a higher fre-quency of treatment failure and higher mortality than whiteAmerican patients [15,16]. Mexican Mestizos commonly showcirrhosis at initial evaluation [17] and patients of Hispanic originare characterized by an aggressive presentation both biochemi-cally and histologically with a very high prevalence of cirrhosisand cholestatic features [18,19], whereas patients of Asian orother non-European Caucasoid background have very poor out-comes [18,20]. Although most of the above mentioned studiesare retrospective and have been performed in tertiary centres,these observations have led to the assumption that AIH hasdiverse clinical phenotypes and outcomes in different ethnicgroups within a country and between countries. These differ-ences may reect genetic predispositions, indigenous etiologicalagents, and/or pharmacogenomic mechanisms, but they mightalso be primarily due to complex socioeconomic reasons suchas variations in the delivery of health care, delayed diagnosis aswell as competing risk factors [21].

1. Prevalence of AIH ranges from 15 to 25 cases per 100,000 inhabitants in Europe and is increasing in both women and men (II-2)AIH can affect all populations and all age groups (II-2)

Clinical spectrum

Clinical features of AIH

In the early 1950s, a novel type of chronic hepatitis with severalparticular features, such as a predilection for young women, aprogressive and usually fatal outcome accompanied by arthralgia,endocrine dysfunction, cutaneous striae and acne, and very highlevels of immunoglobulins in the serum that correlated with anexcess of plasma cells in the liver, was reported rstly by theSwedish physician Jan Waldenstrm [22] and later by Kunkelet al. [23]. In 1955, the lupus erythematosus cell phenomenon

was demonstrated in these patients and therefore, the termlupoid hepatitis was introduced by the group of Ian Mackayin 1956 [24], but ten years later this term was replaced byAutoimmune hepatitis [25], which after a variety of differentterms was accepted in the 1990s by the International AIHGroup (IAIHG) as the nal one [26].

It is now well established that AIH is a clinically distinct syn-drome characterized by a large heterogeneity of clinical, labora-tory and histological manifestations (Table 2). Therefore, AIHshould be considered in any patient with acute or chronic liverdisease, particularly if hypergammaglobulinemia is present, andif the patient has features of other autoimmune diseases(Table 3) [24,2628]. The disease can also affect males (ca.2530% of all AIH patients) and may present at any age and inall ethnic groups [813,2933]. In most studies, a bimodal agepattern at presentation has been reported with one peak duringchildhood/teenage years and another in middle age betweenthe 4th and 6th decade of life [8,11,13,33,34]. Recent studies haveshown that an increasing number of patients are diagnosed alsoat older ages (above 65 years) [3032,35]. Recently it has beenshown that appropriate attention should also be paid to thehealth related quality of life (HRQoL) parameters, since a highrate of previously unrecognised mental impairment with depres-sion and anxiety symptoms are present in patients with AIH [36].

The spectrum of clinical manifestations is variable, rangingfrom no obvious signs or symptoms of liver disease to a severeand almost identical form of an acute or even fulminant episodeof viral hepatitis (Table 2) [3,4,37]. Indeed, approximately 25% ofpatients present with an acute onset of AIH, which is phenotyp-ically similar to acute hepatitis cases of other causes [33,38].However, acute presentation of AIH actually may contain two dif-ferent clinical entities. One is the acute exacerbation of chronicAIH (acute exacerbation form of undiagnosed or misdiagnosedAIH cases) and the other is the genuine acute AIH without chronichistological changes (acute form of AIH; Table 2) [33,3739]. Ofnote, in some patients with acute presentation of AIH,immunoglobulin G (IgG) levels may be within the normal rangeand antinuclear (ANA) and/or smooth muscle antibodies (SMA)as rst screening may be negative and thus, the clinician maynot consider AIH [3,4,34,40,41]. A more extensive and sensitiveautoimmune liver serology testing could be helpful in such cases.Furthermore, in some patients autoantibodies may only becomepositive some months later in the disease course. Some of theseacute cases of AIH may rarely progress to acute liver failure andthis should be kept in mind. The identication of AIH as the aeti-ology of acute hepatitis and/or fulminant hepatic failure is veryimportant because a delay of the diagnosis and thus delay of ini-tiation of therapy results in poorer prognosis of AIH, whereasadministration of immunosuppression with steroids might avoidthe need for liver transplantation (LT) [33,3739,4143].

Commonly (about one third of patients), the clinical presenta-tion is characterized by the presence of one or more of severalnon-specic symptoms listed in Table 2 [8,11,13,18,21,29,33,44,45]. Amenorrhea is also common whereas maculopapular skinrash and unexplained low-grade fever are rare features. Physicalndings may be normal, but sometimes hepatomegaly, occasion-ally painful, splenomegaly and, when frank cirrhosis has devel-oped, signs and symptoms of chronic liver disease like palmarerythema and spider naevi may be found. In advanced stages,the clinical picture of portal hypertension dominates including

Table 1. Grading of recommendations.

I Randomised controlled trialsII-1 Controlled trials without randomisationII-2 Cohort or case-control analytic studiesII-3 Multiple time series, dramatic uncontrolled experimentsIII Opinions of respected authorities, descriptive

epidemiologyAdapted from: [1].


972 Journal of Hepatology 2015 vol. 63 j 9711004

ascites, oesophageal varices and portal hypertensive gastropathy,cytopenias due to hypersplenism as well as hepaticencephalopathy.

Up to a third of patients have an insidious onset and gradualprogression without apparent symptoms at diagnosis (asymp-tomatic) and the nal diagnosis is usually established duringinvestigation for unexplained elevation of serum aminotrans-ferases on routine testing or testing performed for other reasons[8,11,13,29,31,32,44,45]. However, approximately one third ofadult patients and about half of children at diagnosis havealready developed advanced disease with the presence of cirrho-sis, which in most studies is associated with lower overall sur-vival irrespective of the presence of symptoms or not[8,13,29,4447]. The latter nding along with the presence of his-tological evidence of chronic disease on liver biopsy in a propor-tion of patients with acute presentation imply that they probablyhave had subclinical disease for a long time [37,38,42]. Actually,this is one important diagnostic challenge, because subclinicaldisease often precedes the onset of the disease symptoms,whereas long periods of subclinical disease may also occur afterpresentation.

According to the pattern of autoantibodies detected, a sub-classication of the disease into two or three subtypes has been

Table 2. Clinical spectrum of autoimmune hepatitis.

CharacteristicPatients affected Any age (with a bimodal distribution usually with peaks around puberty and between 4th and 6th

decade although a significant proportion of patients are even older (above 65 years of age)) Both sexes (: 3:1) All ethnic groups

Presentation of disease at onset

Broad range from asymptomatic to acute/severe or even fulminant Most common clinical phenotype of the disease (two thirds of patients) is characterized by an insidious

onset either without any apparent symptom or with one or more of the following non-specific symptoms: fatigue, general ill health, right upper quadrant pain, lethargy, malaise, anorexia, weight loss, nausea, pruritus, fluctuating jaundice and polyarthralgia involving the small joints without arthritis, sometimes dating back years

Acute onset of AIH does exist (about 25% of patients); there are two different clinical entities (the acute exacerbation of chronic AIH and the true acute AIH without histological findings of chronic liver disease); centrilobular zone 3 necrosis (central perivenulitis) usually present in patients with acute presentation; autoantibodies or other classical features can be absent; not always responsiveness to corticosteroids

One third of patients at diagnosis have already developed cirrhosis irrespective of the presence of symptoms due to delay in diagnosis

Subclassification AIH-1: the more frequent type of AIH (accounts almost for 90% of AIH cases); detection of ANA, SMA or anti-SLA/LP; association with HLA DR3, DR4 and DR13; any age at onset of variable clinical and histopathological severity; rare failure of treatment but variable relapse rates after drug withdrawal and variable need for long-term maintenance therapy

AIH-2: accounts for up to 10% of AIH cases; detection of anti-LKM1, anti-LC1 and rarely anti-LKM3; association with HLA DR3 and DR7; onset usually in childhood and young adulthood; clinical and histopathological severity commonly acute and advanced; frequent failure of treatment and frequent relapse rates after drug withdrawal; need for long-term maintenance therapy very common

AIH-3: SLA/LP positive, otherwise very similar to AIH-1; often Ro52-antibody positive. Possibly more severe

Physical findings Depend on the clinical status of the disease ranging from completely normal to signs and symptoms of chronic liver disease and/or portal hypertension

Complications HCC development in AIH is less common than in other liver diseases, but it does occur; is strictly associated with cirrhosis suggesting surveillance in all cirrhotic patients with AIH

Drug-related complications are also significant in up to 25% of patients; these are most commonly related to long-term corticosteroids use or azathioprine toxicity and/or drug intolerance

AIH, autoimmune hepatitis; HCC, hepatocellular carcinoma; HLA, human leukocyte antigens; ANA, antinuclear antibodies; SMA, smooth muscle antibodies; anti-SLA/LP,soluble liver antigen/liver pancreas antibodies; anti-LKM1, liver/kidney microsomal antibody type 1; anti-LKM3, liver/kidney microsomal antibody type 3; anti-LC1,antibodies against liver cytosol type 1 antigen.

Table 3. Differential diagnosis of autoimmune hepatitis.

Other autoimmune liver diseases- Primary biliary cirrhosis- Primary sclerosing cholangitis (including small duct primarysclerosing cholangitis)- IgG4-associated cholangitisChronic viral hepatitis- Chronic hepatitis B with or without hepatitis delta- Chronic hepatitis CCholangiopathy due to human immunodeficiency virus infectionAlcoholic liver diseaseDrug-induced liver injuryGranulomatous hepatitisHemochromatosisNon-alcoholic steatohepatitis1-antithrypsin deficiencyWilsons diseaseSystemic lupus erythematosusCeliac disease

JOURNAL OF HEPATOLOGY

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proposed. Initially, two major types, AIH-1 and AIH-2, have beenproposed (Table 2). AIH-1 is characterized by the presence of ANAand/or SMA [3,4,27,28,34,40]. AIH-2 is characterized by thedetection of specic anti-liver/kidney microsomal antibody type1 (anti-LKM1) or infrequently anti-LKM type 3 (anti-LKM3)and/or antibodies against liver cytosol type 1 antigen (anti-LC1)[3,4,27,28,34,40]. This distinction was initially based on circulat-ing autoantibodies alone but thereafter other differences havebeen reported (Table 2). Similarly, the discovery of antibodiesagainst soluble liver antigens (anti-SLA), later found to be identi-cal with previously described antibodies against liver pancreas(anti-LP) and therefore called anti-SLA/LP antibodies, lead tothe denition of a third subtype, AIH-3 (Table 2) [48].Differences between AIH-1 and AIH-3 seemed less pronouncedthan between AIH-1 and AIH-2, but some authors postulatedmore severe disease and the need for lifelong immunosuppres-sion in most if not all AIH-3 patients [4850]. The validity ofthese sub-classications, however, is questionable and subjectof an ongoing debate [3].

Specic clinical features and presentations of AIH

Variant forms of AIH and cholestatic liver diseaseSome patients within the spectrum of AIH present either simul-taneously or consecutively, with clinical, biochemical, serological,and/or histological characteristics of PBC or PSC [51]. Vice versa,some patients with a diagnosis of PBC or PSC show or developfeatures of AIH. So far, several terms have been used to describethese phenomena, in particular overlap syndromes, but also thehepatitic forms of PBC , secondary autoimmune hepatitis,

autoimmune cholangitis, autoimmune sclerosing cholangitis orcombined hepatitic/cholestatic syndromes to describe patientswith features of both AIH and PBC or PSC [5154]. A descriptiveterminology of these variant forms (e.g. PBC with features ofAIH) is probably the most appropriate terminology in the absenceof a clear pathogenetic understanding of these variants.

Internationally agreed criteria dening these variant condi-tions are lacking, and therefore the characteristics of these enti-ties vary between studies making it difcult to givestandardised recommendations. Recently, on behalf of theIAIHG, an international working party critically reviewed overlapsyndromes and found a low sensitivity of the scoring systems forAIH diagnosis (either revised or simplied) in clinically denedoverlap patients [51], which is in keeping with results of previ-ous studies (Table 4) [55]. As a consequence, use of these AIHscoring systems is not generally recommended for the distinctionof these particular patients. Interface hepatitis is a fundamentalcomponent of hepatitis and histology is therefore vital in evaluat-ing patients with overlap presentation. The degree of interfacehepatitis can be considered a measure of AIH-like disease activityirrespective of co-existence or underlying cholestatic liverdisease [51].

The pathogenesis of these variant forms is debated and itremains unclear whether this syndrome forms a distinct entityor a variant of PBC, PSC or AIH. It has been suggested that featuresof AIH develop in patients with immune-mediated cholestaticliver disease and a genetic susceptibility for AIH as shown bythe high prevalence of the AIH-susceptibility HLA-genes DR3 orDR4 in PBC patients with features of AIH, leading to the termsecondary AIH in patients with PBC and overlapping features

Table 4. Specic characteristics and features of autoimmune hepatitis.

CharacteristicClinical features in special conditions

Some patients within AIH spectrum have characteristics of either PBC or PSC (overlap or variant forms); though these conditions really do exist, diagnosis is usually difficult and problematic as internationally agreed criteria are lacking; concurrent cholestatic findings require investigation for AMA and cholangiography (particularly in children - autoimmune sclerosing cholangitis)

Presentation of AIH in pregnant women or more frequently after delivery can occur; the disease usually subsides during pregnancy but post-partum exacerbations are common; maternal and fetal complications are similar to general population

AIH-like disease can arise after liver transplantation for other liver diseases (de novo AIH)Specific characteristics Onset of disease after viral infections (e.g. hepatitis A, Epstein-Barr, human herpes 6, measles) has been

described; AIH should be considered as an alternate emerging diagnosis in cases with previous viral infections followed by unexplained and prolonged hepatitis

Development after administration of drugs, supplements or herbals (drug-induced AIH difficult to differentiate from DILI); nitrofurantoin and minocycline implicated in most cases; treatment with biological agents has been implicated (TNF- blockade) as well as after interferon- for HCV

Concurrent autoimmune or immune-mediated diseases in the patient or first-degree relatives are common (Hashimoto thyroiditis - the strongest association, Graves disease, vitiligo, alopecia, rheumatoid arthritis, diabetes mellitus type-1, inflammatory bowel disease, psoriasis, systemic lupus erythematosus, Sjgrens syndrome, celiac disease, panniculitis, mononeuritis, urticaria pigmentosa, Sweets syndrome, idiopathic thrombocytopenic purpura, polymyositis, hemolytic anemia, uveitis)

An unusual form of AIH occurs in 10-18% of patients with APECED - also known as APS-1AIH, autoimmune hepatitis; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; AMA, antimitochondrial antibodies; IAIHG, International AIH Group; DILI,drug-induced liver injury; TNF, tumour necrosis factor; HCV, hepatitis C virus; APECED, autoimmune polyendocrinopathy candidiasis ectodermal dystrophy; APS-1,autoimmune polyglandular syndrome type 1.



of AIH [56]. In this regard, the name overlap that strongly sug-gests the presence of two distinct diseases could be a misnomer.It should be kept in mind that variant forms of AIH should notbe over-diagnosed in order not to expose PBC or PSC patientsunnecessarily to the risk of steroid side effects.

Features of both AIH and PBC. With no codied diagnosticapproach, reported prevalence gures are variable, but it is gen-erally assumed that the prevalence of AIH-PBC variant is approx-imately 810% of adult patients with either PBC or AIH [57,58].The Paris criteria are currently the most commonly used toolfor diagnosing AIH-PBC variant form as attested by the presenceof at least two of the three accepted key criteria of each diseasenamely, for PBC: 1) alkaline phosphatase (ALP) P2 uppernormal limit (ULN) or c-glutamyl-transpeptidase (c-GT)P5 ULN; 2) presence of antimitochondrial antibodies (AMA);3) a liver biopsy specimen showing orid bile duct lesions; andfor AIH: 1) alanine aminotransferase (ALT) P5 ULN; 2) serumIgG levels P2 ULN or presence of SMA, 3) a liver biopsy show-ing moderate or severe periportal or periseptal lymphocyticpiecemeal necrosis [57]. Indeed, a recent study [59], has shownthat the criteria strictly dened previously by Chazouillereset al. [57] could identify patients with a clinical diagnosis ofAIH-PBC variant with high sensitivity (92%) and specicity(97%). In addition, the 2009 EASL guidelines on the managementof cholestatic liver diseases endorsed these diagnostic criteria,but specied that histologic evidence of moderate to severe lym-phocytic piecemeal necrosis (interface hepatitis) was mandatory.It was stated that these variants should always be consideredonce PBC has been diagnosed and the patient responds poorlyto ursodeoxycholic acid (UDCA) because of potential therapeuticimplications (i.e. the need of immunosuppression) [60].Simultaneous presence of features of both diseases is the usualpresentation, but it should be noted that occasionally the onsetof AIH and PBC is temporally dissociated, usually with PBC pre-senting rst. Interestingly, in most cases, it is possible to deneone primary disorder (dominant disease), usually PBC [51].

Features of both AIH and PSC. The co-existence of features of AIHand features of PSC variant has been described both in childrenand adults and is assumed to exist in a considerable part ofmainly young patients with autoimmune liver disease[5154,61]. Unfortunately, diagnostic criteria for these conditionsare even less well-dened than in AIH-PBC variant cases. As aresult, reported prevalence gures vary greatly but an approxi-mate prevalence of 714% is generally assumed [51]. The diagno-sis of large duct PSC should always be established on typicalcholangiographic ndings, keeping in mind that an intrahepaticbiliary tree which simulates a sclerosing pattern can also beobserved in any liver disease with extensive brosis and nodularregeneration or in cirrhosis [62]. In addition, magnetic resonancecholangiopancreatography (MRCP) may lead to false positivediagnosis due to its limited specicity. Some cases of small ductPSC (normal cholangiogram)-AIH variant forms have also beenreported, but it can be argued that approximately 10% of patientswith typical AIH, with or without ulcerative colitis, may have his-tological features of bile duct injury, thus making this diagnosisparticularly uncertain [63]. In clinical practice, the diagnosis ofAIH-PSC variants is made in a patient with overt

cholangiographic or histological features of PSC, alongside robustbiochemical, serological and histological features of AIH. Itappears that patients with features of AIH and PSC also requireimmunosuppression [64,65].

It should be noted that in children with AIH a specic entityhas been described in almost half of patients characterized bylesions of both AIH and sclerosing cholangitis. Thus, the termautoimmune sclerosing cholangitis (AISC) was introduced byMieli-Verganis group [52] suggesting also the need of an investi-gation of the biliary tree at least with MRCP in all children with adiagnosis of AIH (Table 4) [52,54]. At present, this variant seemsunique for children, as a prospective study in adults with AIH wasnegative and thus, in the absence of cholestatic indices, MRCPscreening does not seem justied in adult-onset AIH [62].However, particularly in young adults with AIH and cholestaticfeatures, and in AIH patients with remaining cholestasis despiteadequate immunosuppression, MRCP for the detection of possibleunderlying or co-existent PSC is recommended.

IgG4-related AIH. In the emerging era of IgG4-related diseases, therole of IgG4 response has been investigated in AIH patients[66,67]. Typically IgG4 disease in the liver manifests as a differen-tial diagnosis of PSC with features of cholangiopathy and jaun-dice. Despite anecdotal reports from Japan, conrmation islacking. Therefore it is difcult to judge, if an entity of AIH-likeIgG4 disease exists and presents a separate disease entity.

In summary, based on the current, very limited knowledgeabout the aetiopathogenesis of AIH, PBC, and PSC, denition ofdiagnostic criteria for these variant forms of AIH are very dif-cult to be established and can only be arbitrary. Consequently,patients with autoimmune liver diseases should rather be catego-rized according to the primary clinical and histological manifes-tation of the disease as AIH, PBC, or PSC, and additionalfeatures of the respective other immune-mediated liver diseaseshould be listed as such (e.g. PBC with features of AIH). In addi-tion, the low prevalence of these variants has made it impracticalto perform randomised controlled trials for their management.However, as these variant conditions do occur quite frequently,specic therapeutic considerations may be required in patientswith PBC or PSC with features of AIH [68]. In general, featuresof AIH should be managed like AIH, as untreated AIH has a poorprognosis, but response to therapy is generally very good.

DILI and AIHThe relationship between DILI and AIH is complex and not fullyunderstood. In principle, three scenarios are possible [69,70]:

1. DILI with a strong immunoallergic component mimicking AIH2. AIH mimicking as DILI due to drug exposure in recent weeks

and spontaneous improvement after cessation of drugexposure

3. AIH triggered by an offending drug (DILI-induced AIH)

It appears that all three scenarios occur. As both immunoaller-gic DILI and AIH are presumably mediated by specic immunereactions to antigens in hepatocytes, clinical and histologicaloverlap between these conditions is not surprising.Nonetheless, the differential diagnosis between these conditions



and the implications for the pathogenesis of AIH are bothimportant.

Drug-induced AIH has been particularly well described fordrugs no longer in use such as tienilic acid and dihydralazine[71,72]. Reactive metabolites created through hepatic metabo-lism of drugs have been shown to bind to cellular proteins suchas components of CYP450, i.e. CYP2C9 in the case of tienilic acidand CYP1A2 in the case of dihydralazine. These can then be rec-ognized by the immune system as neoantigens [71,72]. Amongdrugs still widely used, drug-induced AIH has been well docu-mented for nitrofurantoin and minocycline [73]. When compar-ing patients with drug-induced AIH to those with genuine AIH,the two groups were found to have quite similar clinical and his-tological patterns, although the former has lower histologicalactivity and does not seem to require long-term immunosuppres-sion [74].

Histologically distinguishing DILI from AIH remains a chal-lenge. A recent study has suggested that sufcient differencesexist so that pathologists can use the pattern of injury to suggesta correct diagnosis in many cases [75]. Nevertheless, the differen-tiation is often very difcult, because DILI lacks a reliable diag-nostic test and, like AIH, the diagnosis is mainly based onclinical and serological grounds [76]. Although the frequency ofdrug-induced AIH-like syndrome is difcult to be assessed, itcan account for approximately 912% of cases with classical fea-tures of AIH [74,77]. An important element in the identication ofthis syndrome is the patients history that should focus on recentexposure to drugs that can induce AIH-DILI [74]. In 30% of cases itcan be associated with features of hypersensitivity such as fever,rash and eosinophilia [78]. The absence of cirrhosis at presenta-tion can also be an element in favour of AIH-DILI [78]. SevereAIH-DILI usually responds to high doses of steroids in the sameway as severe AIH, if treatment is started without delay.Sometimes only the follow-up can differentiate between AIHand DILI: steroid treatment can be discontinued without relapsein DILI, whereas in genuine AIH relapse will occur universally, ifimmunosuppression is stopped within a few months. A trial ofsteroid treatment and close observation upon steroid taperingand possible withdrawal is therefore recommended for uncertaincases (see treatment algorithm Fig. 1).

AIH and pregnancyThe disease is very rarely diagnosed during pregnancy, but, likeother autoimmune diseases, may notably manifest in the post-partum period. In patients with known AIH, improvement oreven spontaneous remissions during pregnancy can be observed,while ares after delivery are frequently observed [7984]. This ispresumably due to immune reconstitution following delivery.Therefore, the possibility of AIH should be strongly consideredin the differential diagnosis of liver dysfunction, particularlyaccompanied by hypergammaglobulinemia with selective IgGelevation, in the post-partum period, but even during pregnancy,as ares can also occur anytime during pregnancy. Effectiveimmunosuppression has enabled the occurrence of pregnancyin young females with AIH presenting initially with amenorrhea,and immunosuppression should almost always be continued dur-ing pregnancy with generally good pregnancy outcome.

Viral hepatitis and AIHIt has been suggested, that in susceptible individuals, AIH may beinduced by viral infections, and a number of possible cases have

been reported [3,4,85,86]. Molecular mimicry between viral epi-topes and epitopes of autoantigens have supported the concept ofvirally induced AIH. On the other hand, the few cases reportedmight also represent a diagnostic bias in two forms: rstly,patients with subclinical AIH previously overlooked may becomediagnosed when suffering from an acute incidental viral hepati-tis; secondly, patients with acute AIH and marked hypergamma-globulinaemia might display false positive results on serology forviral markers. On the other hand, the development of AIH, or offeatures of AIH, has also been reported in some patients withhepatitis C virus (HCV) after treatment with interferon-alpha[87,88] and rarely in acute HCV infection even after viral clear-ance [89]. The differentiation between AIH and chronic HCVwas a challenge in the past, particularly because of the immunos-timulatory side effects of interferon-alpha, but due to the adventof interferon-free treatment regimens, this represents no longer adifcult clinical problem: HCV infection should be treated pri-marily, and if inammatory liver disease persists, the diagnosisof AIH should be considered.

De novo AIH in liver transplant recipientsAIH, or an AIH-like syndrome, can develop after LT undertakenfor other liver diseases, both in adults and children. This situationhas been called de novo AIH [90,91], although it has been sug-gested that alternative nomenclature such as post-transplantimmune hepatitis or graft dysfunction mimicking AIH or post-transplant plasma cell hepatitis may be more appropriate as thetransplanted hepatocytes are not strictly self and thus the con-ditions not strictly autoimmune [5,92]. Nevertheless, thetimely recognition of this entity appears to be helpful for avoid-ing graft rejection, and the need for another LT and for improvinglong-term survival, as these patients benet from increased

Probable or possible AIH vs. DILI

0.5-1 mg/kg predniso(lo)ne

Response

Relapse

Definite AIH

Non-response

Consider alternative diagnoses

Taper steroids until withdrawal

Treatment of AIH

No relapse

DILI*

Avoid this drug in future

Fig. 1. Suggested diagnostic algorithm for autoimmune hepatitis usingroutine autoantibody testing by indirect immunouorescence (IFL) andenzyme linked immunosorbent assay (ELISA) testing with a set of fourautoantibodies. A liver biopsy is always required for the demonstration ofinammatory hepatitis, as well as for staging and grading of the liver disease.Long-term follow-up is advised in order not to miss a late relapse of AIH (e.g. 6monthly for 3 years).



immunosuppression including steroids and azathioprine like ingenuine AIH [90].

Associated autoimmune conditionsAIH is associated with the presence of a wide variety of otherautoimmune or immune-mediated diseases (Table 4)[8,13,29,45,9396]. Actually, concurrent autoimmune diseasesare common in patients with AIH and mirror the full range ofknown autoimmune diseases. Therefore, an extended diagnosticscreening for other autoimmune diseases, especially autoimmunethyroiditis, seems reasonable in patients with AIH, both at diag-nosis and at regular intervals during follow-up [95]. In additionto the patient being affected by immune-mediated diseases, theiroccurrence is also more frequent in rst-degree relatives of AIHpatients, and therefore a careful family history should be under-taken. A careful personal and family history may also help inidentifying rare variants of AIH due to autosomal recessivegenetic aberrations such as the autoimmune polyendocrinopa-thy-cadidiasis ectodermal dystrophy syndrome (APECED) alsoknown as autoimmune polyendocrinopathy syndrome type 1(APS-1) which is caused by mutations in the autoimmune regula-tor gene (AIRE) and characterized by chronic mucocutaneouscandidiasis, ectodermal dystrophy and autoimmune destructionof several endocrine organs, leading mainly to hypoparathy-roidism, adrenocortical failure and gonadal failure in females(Table 4) [8,13,29,45,9396].

Complications of AIH

In principle the complications of AIH are the same as in any otheracute or chronic progressive liver disease. In acute presentationsthe risk of liver failure and infectious complications are predom-inant and may be aggravated by immunosuppressive treatment.In chronic disease, especially in patients undiagnosed or insuf-ciently treated, complications of cirrhosis occur. In particular,hepatocellular carcinoma (HCC) is a known consequence ofAIH-related cirrhosis although its occurrence in association withAIH is signicantly less frequent compared to most other causesof liver cirrhosis (Table 2) [3,11,13,97,98]. A recent population-based study showed that the risk of hepatic and extra-hepaticmalignancy was signicantly increased in AIH patients [99].Studies from Denmark, Germany, Netherlands, UK, USA andJapan identied male gender as a particular risk factor, and thepresence of cirrhosis was a universal prerequisite for HCC devel-opment, which was observed in the at risk cirrhotic population ata rate of 12% per year [11,13,97,98,100102]. Surveillance rec-ommendations have not been validated in AIH and cirrhosis,but as the HCC risk appears to be signicant, liver ultrasonogra-phy every six months in patients with cirrhosis appearsreasonable.

In addition to complications of the liver disease, complicationsof long-term immunosuppression need to be considered, and thetwo risks may associate. Of note, extra-hepatic malignancies ofdiverse cell types occur in 5% of patients in an unpredictable fash-ion with non-melanoma skin cancers being the most common[99,103]. It is likely that this risk is primarily due to the long-termimmunosuppression required in most patients. To what extentthe risk for extra-hepatic malignancy is different from the normalpopulation is poorly studied. Nonetheless, it appears sensible toapply routine health screening measures for other malignanciesin AIH patients.

2. AIH should be considered in any patient with acute or chronic liver disease, particularly in the context of hypergammaglobulinemia (II-2)

3. Prompt and timely diagnosis is crucial as untreated AIH has a high mortality rate (I)

4. Approximately 1/3 of adult patients and about 1/2 of children with AIH have cirrhosis at presentation (II-2)

5. Acute presentation of AIH can occur and may manifest as acute exacerbation form of previously undiagnosed AIH or new onset acute AIH without histological changes suggestive of chronic disease (II-2)

6. AIH is associated with a broad variety of other autoimmune diseases (II-2)

7. All children with a diagnosis of AIH should undergo (MR-) cholangiography to exclude autoimmune sclerosing cholangitis (II-2)

8. AIH patients with cirrhosis should undergo liver ultrasound in six-month-intervals for HCC screening(II-2)

9. Counselling for UV-protective measures should be considered for patients on immunosuppressants. Dermatological monitoring for non-melanoma skin cancer after long-term immunosuppressant treatment may be considered (III)

Diagnostic work-up and diagnostic criteria

The diagnosis of AIH is usually based on the presence of the typ-ical phenotype of the disease along with the exclusion of othercauses of chronic liver diseases (Tables 2 and 4). The diagnosticcriteria for AIH and a diagnostic scoring system have been codi-ed by a group of experts in the IAIHG in 1993 [26], revised in1999 [27] and more recently proposed in a simplied mannerfor routine clinical use (Table 6) [28].

Obvious features raise the suspicion of AIH and the applica-tion of published criteria (Tables 5 and 6) allows a ready diagno-sis [26]. Unfortunately, in a considerable proportion of cases, thediagnosis is challenging and referral to hepatologists with specicclinical expertise in AIH may be warranted. In patients with aninsidious onset and gradual progression without apparent symp-toms, the diagnosis relies predominantly on laboratory ndings.Therefore, the diagnostic work-up rests on such central elementsas circulating non-organ specic autoantibodies associated withpolyclonal hypergammaglobulinemia and typical or compatiblehistology in the absence of viral hepatitis markers. Histology isalso essential in making the diagnosis.

Laboratory ndings

A predominantly hepatitic pattern, with bilirubin concentrationsand aminotransferases ranging from just above the upper limitsof normal to more than 50 times these levels, with usually nor-mal or only moderately elevated cholestatic enzymes, is the typ-ical biochemical prole of the disease [4,2628]. However, the



degree of ALT elevation does not reliably reect severity of AIH atthe histological level. Of interest, recent studies have shown thatalong with the elevations of aminotransferases, c-GT levels butnot ALP can also be increased in AIH and furthermore, might beused as independent predictor of treatment outcome [29,45]. Inkeeping with the uctuating nature of the disease, the amino-transferases and c-GT levels may even spontaneously normalise(spontaneous biochemical remission), despite histological evi-dence of persisting inammatory activity, sometimes even severeinammation. Such spontaneous apparent biochemical remis-sions are a critical issue that may sometimes result in delayand/or underestimation of the diagnosis, since reappearance ofclinical disease may only become obvious several months oryears later, or may even be completely asymptomatic. This dis-ease behaviour may sometimes explain the presence of alreadyestablished cirrhosis in almost one third of patients at the timeof initial diagnosis.

Increased serum c-globulin or IgG levels are found in approx-imately 85% of patients with AIH even in the absence of cirrhosis[29,104,105]. This prevalence tends to be lower in patients withan acute onset of the disease, in which a higher proportion ofpatients (25% to 39%) with normal IgG levels has been reported[106,107]. The presence of high IgG levels is a very distinctivefeature (IgA and IgM levels are usually normal) [28]. IncreasedIgA or IgM levels suggest different diseases such as alcoholicsteatohepatitis and PBC, respectively.

It is important to underline that the range within which c-globulins and IgGs are considered normal is wide. This mayexplain why a proportion of patients may show apparently nor-mal IgG levels at diagnosis. Many, if not most of these patientshave IgG levels in the upper range of normal, and show a markedfall upon initiation of therapy, sometimes even to levels belowthe normal range. These patients have a relative increase of theirIgG levels considering their very low natural IgG levels but arestill within the statistical normal range hampering initial diagno-sis. The drop in IgG levels observed during treatment seems toconrm this hypothesis. Indeed, the level of immunoglobulinsis an important and useful marker in monitoring the responseto treatment and the achievement of remission. Reaching normallevels of immunoglobulins has been shown to correlate well withthe improvement of inammatory activity, even if sometimes amild inammatory activity (hepatitis activity index (HAI) 56)may coexist with normal IgG levels [108]. Normalisation of bothtransaminase levels and IgG levels has therefore been agreedupon as diagnostic marker of full biochemical remission [34].

The absence of viral markers is one of the four elementsincluded in the simplied diagnostic criteria for AIH [28], but incountries with a high prevalence of viral hepatitis co-existenceof AIH and viral hepatitis may exist [109111]. In these casesthe diagnosis of AIH may be overlooked and AIH could remainuntreated, if absence of viral hepatitis is considered a prerequisitefor making the diagnosis AIH. Usually AIH has a more aggressivecourse and more severe prognosis than viral hepatitis (either B orC) and a careful evaluation of the liver biopsy along with liverautoimmune serology testing can help in identifying the co-exis-tence of a double mechanism of liver damage. With the advent ofinterferon-free regimens for the treatment of HCV infection, thepossibility of treating both AIH and viral hepatitis has become

Table 5. Summary of the criteria for the diagnosis of autoimmune hepatitis, on which the 1999 International Autoimmune Hepatitis Group (IAIHG) diagnostic scorewas based [27].

Definite AIH Probable AIHNormal -1AT phenotype Partial -1AT deficiencyNormal ceruloplasmin level Non-diagnostic ceruloplasmin/copper levelsNormal iron and ferritin levels Non-diagnostic iron and/or ferritin changesNo active hepatitis A,B,C infection No active hepatitis A,B,C infectionDaily alcohol 1:80, in adults and >1:20 in children ANA, SMA, anti-LKM1 >1:40 in adultsAMA negative Other autoantibodiesLiver histology Liver histology

Interface hepatitis moderate to severe Interface hepatitis moderate to severeNo biliary lesions, granulomas or prominent changes suggestive of another disease

No biliary lesions, granulomas or prominent changes suggestive of another disease

Table 6. Simplied diagnostic criteria of the International AutoimmuneHepatitis Group [28].

Feature/parameter Discriminator ScoreANA or SMA+ 1:40 +1*ANA or SMA+ 1:80 +2*or LKM+ 1:40 +2*or SLA/LP+ Any titer +2*IgG or -globulins level >upper limit of normal

>1.1x upper limit+1+2

Liver histology (evidence of hepatitis is a necessary condition)

Compatible with AIHTypical of AIHAtypical

+1+20

Absence of viral hepatitis NoYes

0+2

Denite autoimmune hepatitis: P7; Probable autoimmune hepatitis: P6.Addition of points achieved for all autoantibodies (maximum, two points).Typical liver histology for autoimmune hepatitis = each of the following featureshad to be present namely, interface hepatitis, lymphocytic/lymphoplasmacyticinltrates in portal tracts and extending into the lobule, emperipolesis (activepenetration by one cell into and through a larger cell), and hepatic rosette for-mation. Compatible liver histology for autoimmune hepatitis = chronic hepatitiswith lymphocytic inltration without all the features considered typical.Atypical = showing signs of another diagnosis, like steatohepatitis.



much easier, and in milder cases HCV infection should be treatedrst and then liver disease reassessed.

Autoantibodies

Autoantibodies are the hallmark of AIH and represent an impor-tant part of the diagnostic work-up. Indirect immunouorescence(IFL) is the preferable and main technique for routine autoanti-body testing [112] for all autoantibodies except anti-SLA/LP anti-bodies (Fig. 2). It should be performed on freshly frozen rodentsubstrate that usually includes kidney, liver and stomach. Thiscombination allows detection of ANA, SMA, anti-LKM1, as wellas the rare antibodies anti-LC1 and anti-LKM3, if anti-LKM1 isabsent. At the same time, AMA are also reliably detected by initialIFL screening and can thus help detect co-existent or variantforms of AIH-PBC. Positive sera should be titrated up to extinc-tion. In adults, signicant titers are P1:40 dilution by IFL. In chil-dren, titers of 1:20 for ANA or SMA and 1:10 for anti-LKM1 arealready strongly supportive of the diagnosis of AIH when usedin combination with other laboratory and clinical features sug-gestive of the disease [54]. Other immunochemical techniqueslike ELISA or immunoblotting are available for the search ofautoantibodies such as anti-LKM1, anti-LKM3, anti-LC1 and theonly diagnostic tests for anti-SLA/LP, whose exact target antigenshave been identied on a molecular level and are used in solidphase assays [4,112,113].

ANA and SMA are markers of AIH-1, which account for about75% of patients [8,11,29], but are not disease specic and showa wide range of heterogeneity in terms of antigenic specicity,

together with a broad spectrum of titers. The uorescence patternof ANA in AIH is usually homogeneous using Hep2 cells but speck-led pattern is not infrequent. The antibody is found in 43% of AIH-1 patients [29], and is associated with a variety of antigenic speci-cities including histones, double-stranded DNA (15%), chromatinand ribonucleoprotein complexes. However, no single pattern orcombination is pathognomonic of AIH, whereas investigation fordifferent staining of ANA patterns seems to have no practical clin-ical implications and diagnostic relevance in routine clinical prac-tice and, therefore, the use of Hep2 cells at the screening stage ofAIH is not recommended [112114]. SMA reacts to severalcytoskeletal elements including F-actin with a reported preva-lence of anti-actin antibodies in 41% of patients.When kidney sec-tions are utilised as a substrate for IFL SMAvg (vessel/glomeruli)and SMAvgt (vessel/glomeruli/tubules) patterns can be identied,which are frequently associated with, but not pathognomonic of,AIH. They correlate with F-actin antigenicity [112]. In the diagnos-tic work-up for AIH, SMA/anti-actin antibody testing is appropri-ate and may also be done by ELISA [114,115]. However, IFLremains superior to ELISA and provides the best specicity/sensi-tivity compromise for testing for SMA. In fact, actin is not the onlytarget antigen of AIH-specic SMA reactivity and thus ELISA canmiss the diagnosis in about 20% of cases [4,112,113,116118].ANA and SMA re-activities frequently coexist in the same serumand this improves the strength of the diagnosis.

Anti-LKM1 and/or anti-LC1 are the serologic markers of AIH-2.The two antibodies often coexist and in a series of 38 AIH-2patients, the reported prevalence was 66% for anti-LKM1 and53% for anti-LC1, respectively [29]. Unlike the antigen

Liver disease of unknown origin

IFL autoantibody test on rodent tissue sections

+ SLA/LP (ELISA or blot)

ANA+ SMA+ LKM1/LC1+ Test negativeSLA/LP+

Consider AIH* Clinical suspicion* remains

Consider alternate diagnoses or

autoantibody-negative AIH

Repeat testing in specialty lab (including pANCA and specific

immunoassays for LKM1, LKM3, LC1, SLA/LP, F-actin,

Ro52, gp 210**, sp100**)

Consider AIH

Liver biopsy

Positive

Negative

Fig. 2. A case based algorithm for patients with a suspicion of autoimmune hepatitis or drug-induced liver injury (DILI) using a response guided approach. Test alsofor elevated IgG-levels. These antibodies are highly specic for the diagnosis of PBC.



heterogeneity seen for ANA and SMA the major target autoanti-gen of anti-LKM1 has been clearly identied as the cytochromeP4502D6 (CYP2D6) and the formiminotransferase cyclodeami-nase (FTCD) for anti-LC1. Despite a well characterized target anti-gen, neither anti-LKM1 nor anti-LC1 are disease specic, as theyhave been described in a small proportion (510%) of adult andpaediatric patients with chronic HCV infection [87,88,119123].The presence of homology sequences between CYP2D6 and HCVproteins is the basis for the appearance of anti-LKM1 antibodyin HCV patients who are genetically susceptible for AIH (mainlyDRB107 positive) through a mechanism of molecular mimicry[124]. Homologies of the target antigen of anti-LKM1 antibodieswith other viral proteins have also been observed [5]. Also,anti-LKM1 antibodies have been described in a liver transplantrecipient transplanted for Wilsons disease following rejectionepisodes [125].

Anti-SLA/LP is the only disease specic autoantibody andtherefore it has high diagnostic value. The target antigen has beenidentied as a synthase (S) converting O-phosphoseryl-tRNA(Sep) to selenocysteinyl-tRNA (Sec), whose terminological correctlabel is SepSecS [126,127]. This has led to the development ofreliable commercial assays for anti-SLA/LP detection (ELISA anddot-blot) [126,128]. Anti-SLA/LP is detected in approximately30% of patients with AIH more commonly associated with con-ventional autoantibodies, and is often associated with anti-Ro52 antibodies [128132], but sometimes it is the only autoan-tibody reactivity detectable. Its presence may identify patientswith more severe disease and worse outcome [49,50,133,134]though these prognostic associations are controversial [129,132].

Further autoantibody testing may be helpful, in particular forthose patients testing initially negative in the above assays.Antineutrophil cytoplasmic antibodies (ANCA) are detected usingethanol-xed human neutrophils with serum diluted 1:20.Atypical pANCA antibodies, originally considered specic of PSCand inammatory bowel disease, are also frequently present inpatients with AIH-1 [135,136]. Recent evidence indicates thatthe target antigen is located in the nuclear membrane and for thisreason some authors describe these antibodies as perinuclearanti-neutrophil nuclear antibodies (p-ANNA) [137,138]. Theirpositivity can be an additional element used towards the diagno-sis of AIH, particularly if other autoantibodies are negative[27,112]. AMA, the specic serologic marker of PBC diagnosis,can be occasionally detected (812%) [139,140] in patients withthe classical phenotype of AIH without any other evidence ofPBC, and may hint at co-existent or underlying PBC.Nonetheless, these patients should be classied and treatedaccording to their clinical phenotype.

Autoimmune serology remains the Achilles heel in the diag-nostic work-up for AIH. In fact IFL using rodent tissue, whichhas been indicated by the committee for autoimmune serologyof the IAIHG as the best technique for the detection of autoanti-bodies is time-consuming, requires experienced technicians andis insufciently standardised. Indeed, in real life the developmentof in-house validated sections for IFL does not seem to be feasible.Commercial substrates are also available; their quality howeveris variable. These are treated with xatives in order to lengthentheir shelf life, but this also causes enhanced background stainingwhich can potentially cause difculties in the interpretation ofuorescence patterns.

Therefore, methods other than IFL, like ELISA, are gaining pop-ularity. This shift has been supported by the introduction of

assays based on recombinant/puried target antigens (CYP2D6,FTCD, SLA/LP, and F-actin). However, the use of ELISA as the soleprimary screening test for AIH-related autoantibodies is inappro-priate because there is no useful combination of molecular speci-cities for a dependable detection of ANA and SMA, while theresults are interchangeable with IFL for those autoantibodies(anti-LKM1, anti-LC1) whose target antigen has been identiedat the molecular level [141]. Fig. 2 provides an algorithm forautoantibody testing in AIH.

Autoantibody titers and specicity may vary during thecourse of the disease, and seronegative individuals at diagnosismay express the conventional autoantibodies later in the diseasecourse [142,143]; in fact, repeated testing may allow autoanti-body detection and, thus, correct disease diagnosis and classica-tion [27,112,113]. In adults, autoantibody titers correlate onlyroughly with disease activity, clinical course and treatmentresponse [144] and, therefore, they do not need to be monitoredregularly unless a signicant change in the clinical phenotypedoes appear. However, in paediatric patients, autoantibody titersmay be useful biomarkers of disease activity and can be used tomonitor treatment response [145]. In particular anti-LC1 anti-bodies have been shown to correlate well with disease activityshowing a signicant decrease in titer (>50%) or disappearanceduring remission and are up during relapse [146].

The detection of autoantibodies plays a pivotal role in thediagnosis of AIH. Laboratory personnel and clinicians need toincrease their expertise with disease expression and theinterpretation of liver autoimmune serology in order to derivemaximal benets for patients. Tests must be ordered speci-cally on the basis of reliable clinical data and test results mustnot be interpreted outside the specic clinical context. Onlythen, can sensible evidence-based decisions be made, and thepotential of serological work-up be exploited to the benet ofthe patient. Finally, complete work-up for autoimmuneserology is not available in all laboratories; it is important toidentify laboratories, which are able to fully characterizepatients sera, and patient sera should be sent to such referencelaboratories for full evaluation especially in cases of diagnosticuncertainty.

Histology

Liver biopsy is considered a prerequisite for the diagnosis of AIH[2628]. Apart from diagnosis, it is used to guide treatment deci-sions and should be performed before starting treatment, pro-vided there are no contraindications [27,28]. When severecoagulopathy is present the transjugular approach can be used,in particular, in acute/fulminant onset of the disease.Alternatively, biopsy under visual control by mini-laparoscopyhas also been shown to be safe [147] even in cases of advancedcoagulopathy [148], and may yield additional information[147,149]. Interface hepatitis (hepatitis at the portal-parenchy-mal interface) with dense plasma cell-rich lymphoplasmocyticinltrates, hepatocellular rosette formation, emperipolesis(active penetration by one cell into and through a larger cell)and hepatocyte swelling and/or pycnotic necrosis are the typicalhallmarks of AIH [28,150,151]. Plasma cells are typically abun-dant at the interface and throughout the lobule, but their paucityin the inammatory inltrate (34% of cases) does not precludethe diagnosis [150,152,153]. However, there is no morphologicalfeature that is pathognomonic of AIH. Interface hepatitis is not



disease specic and patients with drug-related, viral or immune-mediated disease may show similar features.

Panlobular hepatitis, bridging necrosis and massive necrosisall of which are signs of severe inammatory activity, are presentless commonly but are part of the histological spectrum [27] andmay occur in acute disease onset. The characteristic histologicalpattern is panacinar hepatitis (parenchymal collapse) especiallyin biopsies performed during an acute onset and closely resem-bles drug-induced hepatitis [154,155]. Alternatively pericentral(Rappaport zone 3) necrosis may be present, which also resem-bles acute toxic injury [107,156,157]. These histological lesionshave recently been proposed by the US NIH Acute Liver FailureStudy Group as a set of diagnostic criteria for AIH presented asacute liver failure [37]. Additional features in cases of acute liverfailure due to AIH include the presence of portal lymphoid folli-cles, a plasma cell-enriched inammatory inltrate and centralperivenulitis [37,107]. Transition from pericentral hepatitis tointerface hepatitis has been demonstrated in sequential biopsiesfrom patients with acute disease onset [158]. These observationssuggest that the perivenular pattern of injury may be an earlyhistological manifestation of AIH that is missed in biopsiesobtained later in the course of the disease. Other lesions suchas granulomata, cholangitis, steatosis or steatohepatitis can beseen, but if prominent they reduce the probability of the diagno-sis of AIH. An inammatory lymphocytic inltrate of bile ductshas been described in 10% of cases but such individuals usuallylack clinical, serological and immunological features of PBC, andthey respond to corticosteroid therapy as patients with classicalAIH [63,159]. At the time of diagnosis different stages of brosisare present and about one third of patients already display estab-lished cirrhosis [150,151,160]. Macroscopic assessment by mini-laparoscopy increases the detection rate of cirrhosis by up to onethird, as the macronodular nature of AIH cirrhosis may lead tofalse negative biopsy results missing the brous septa betweenregenerative nodules [147,161]. Of interest, the histological fea-tures of necroinammatory activity and severity of AIH are oftennot in parallel with the biochemical activity of the disease[27,28,34,40]. Liver biopsy, therefore, provides information onprognosis and management as for instance the presence of cir-rhosis may inuence the choice and dose of the immunosuppres-sive agents prescribed while suggesting the need for regularscreening for complications, such as oesophageal varices andHCC. It is highly recommended to have the histology reviewedby an experienced liver histopathologist who should discuss themost difcult cases with the clinician. The pathologist shouldweigh the inammatory activity with the aid of the HAI scorein order to give a quantitative evaluation of the inammatoryprocess to be monitored during treatment and follow-up.Despite the growing interest for non-invasive methods for theassessment of brosis and inammation, most studies with thesetechniques have been performed in the eld of viral hepatitis Cand very few data are available on AIH. The limits for the clinicaluse of these methods in AIH, in particular Fibroscan, are related tothe interference of necroinammatory activity in the orid phaseof the disease and to the overlap of adjacent stages of brosis[162]. A recent proposed non-invasive diagnostic score to predictinammatory activity and severity of brosis based on routinelaboratory parameters in AIH provides a useful tool for monitor-ing disease activity during treatment but cannot at present sub-stitute the need of a biopsy, particularly at diagnosis [163].

Diagnostic scoring criteria

A comprehensive scoring system which grades every clinical, lab-oratory and histological feature of AIH, including response to cor-ticosteroid treatment, has been published in 1999 by the IAIHG[27]. This scoring system was initially developed to dene homo-geneous cohorts of AIH patients for clinical trials rather thandiagnosing AIH in individual patients. This scoring system hasbeen validated in several papers [164166] and, although devel-oped as a research tool to provide comparability among popula-tions in clinical trials, it has been widely used in clinical practicein assessing patients with few or atypical features of the diseasenot readily captured by the descriptive criteria [167]. The typicalfeatures, on which the diagnostic score is based, are summarizedin Table 5. The drawbacks of this scoring system as a clinical toolare its complexity and failure to consistently distinguish AIHfrom cholestatic syndromes. In 2008, a simplied scoring systemdesigned for every day clinical practice was proposed by theIAIHG [28]. It is based on four parameters: presence and titer ofautoantibodies detected by IFL or ELISA (for anti-SLA/LP), serumIgG concentration, presence of typical or compatible histology,and absence of viral hepatitis markers (Table 6). Compared withthe original revised score system the simplied score has some-how lower sensitivity (95% vs. 100%) but higher specicity (90%vs. 73%) and accuracy (92% vs. 82%) [55,166,168,169] and, accord-ing to some studies, seems to work well in patients with AIH-PBCvariant [168,170]. It does not grade response to corticosteroidtherapy [169] whose inclusion has been advocated as an addi-tional criterion, but is primarily meant to serve as a guide forthe initiation of treatment, at which time point information onresponse can naturally not be available. The simplied scoringsystem is useful in excluding AIH in patients with other condi-tions and concurrent immune features [166,170], but it is morelikely to result in the exclusion of atypical cases [166,169,171].Prospective evaluation of these criteria is required to corroboratethese observations.

In conclusion, the simplied criteria are user-friendly and agood tool for daily clinical practice but without a diagnostic goldstandard the clinicians must regard any diagnostic score only asan aid to diagnosis of AIH [172] and the criteria should be usedalongside clinical judgement. In this context, a subgroup ofpatients especially those with acute or fulminant onset of AIHmay be missed by standard diagnostic criteria and thereforerequire special attention. Acute or fulminant AIH is characterizedby an abrupt onset of symptoms and frequently with acute liverfailure. The challenge in the diagnosis is related to the lack of awidely accepted denition [173] and of the phenotype character-istic of AIH. In fact, 25% to 39% of patients with acute onset AIHhave normal levels of IgG [106,107] while 9% to 17% test negativefor circulating autoantibodies [39,106]. The higher percentage ofthose patients with normal IgG in this setting can be explained bythe short duration of the inammatory process. A liver biopsy isessential although the classical lesions pathognomonic of AIH arefrequently lacking and the most prominent lesion is the pericen-tral necrosis [37,156158]. So far, few data are available on theuse of the published scoring systems in acute onset of AIH[169,174]. In 70 patients with fulminant liver failure, the revisedscoring system supported the diagnosis of AIH in 40% of cases,whereas only 24% were identied by the simplied scoring sys-tem [169]. In another series of 55 patients with acute/fulminant



onset 91% had a score compatible with AIH with the revised scor-ing system vs. 40% with the simplied version [174]. The use ofthe diagnostic scoring systems in this setting of patients shouldbe further evaluated prospectively.

Treatment of AIH

The aim of treatment in AIH is to obtain complete remission ofthe disease and to prevent further progression of liver disease.This requires mostly permanent maintenance therapy, or (onlyachievable in a minority of patients) induction of a sustainedremission following treatment withdrawal.

The current immunosuppressive treatment regimens arebased on studies that were mostly published in the 1970s and80s [175179]. These studies revealed that untreated, moderateto severe AIH (conuent necrosis on liver biopsy, AST levels>5 times the ULN, c-globulin levels >2 ULN) had a very poorprognosis and have demonstrated that immunosuppressive ther-apy improves liver functions tests, ameliorates symptoms andprolongs survival. As these studies were performed before dis-covery of the HCV they are likely to have included patients withviral hepatitis C.

The benets of immunosuppressive treatment in asymp-tomatic older patients with mild necroinammatory activity onliver biopsy are not well established in terms of clinical endpointsand their management remains controversial (Fig. 3). Treatmentrelated side effects should be counterbalanced to the risk of sub-clinical disease progression and evolution into symptomatic dis-ease as well as the prospect of a complete and sustained responseto treatment. Ten-year survival in untreated patients with milddisease was reported to be 6790% [180,181], and in an uncon-trolled study untreated asymptomatic patients had similar sur-vival to those receiving immunosuppression [44]. Thus, adecision not to treat might be justied, especially if there are rel-ative contraindications to the use of steroids. In addition, sponta-neous resolution of AIH may occur [182]. However, it also has tobe acknowledged that untreated AIH has a uctuating, unpre-dictable disease behaviour and a substantial proportion ofasymptomatic patients become symptomatic during the courseof their disease follow-up [44,183], and progression towards

10. AIH is a clinical diagnosis. The diagnosis of AIHrelies particularly on the presence of autoantibodies,hypergammaglobulinemia and typical or compatiblehistology (II-2)

11. The presence of elevated IgG levels, especially in theabsence of cirrhosis, is a distinctive feature of AIH. Aselectively elevated IgG in the absence of IgA and IgMelevation is particularly suggestive of AIH (II-3)

12. Normal IgG or -globulin levels do not preclude thediagnosis of AIH. Most of these patients demonstrate a fall of IgG levels upon treatment (III)

13. Circulating non-organ specific antibodies are present inthe vast majority of AIH patients. Autoantibody profiles have been used for sub-classification of AIH.- AIH-1 (ANA and/or SMA positive) - AIH-2 (LKM1, LKM3 and/or LC-1 positive)- AIH-3 (SLA/LP positive).The clinical implications arising from this sub-classification are uncertain (II-2)

14. Indirect immunofluorescence is the test of choice for the detection of ANA, SMA, LKM and LC-1.Immunoassays (ELISA/Western blotting) are the testsof choice for the detection of SLA/LP. Methods and cut-off values should be reported by the laboratory (III)

15. Histological demonstration of hepatitis is a prerequisite for the diagnosis of AIH and needs to be part of the initial diagnostic work-up (II-2)

16. There are no morphological features that are pathognomonic of AIH, but interface hepatitis, periportal necrosis, emperipolesis and rosetting of hepatocytes are suggestive of AIH. These features should be reported by the pathologist in addition to grading (hepatitis activity index) and staging of disease(II-2)

17. Pericentral necrosis may be present in the acute onsetof AIH and histologically indistinguishable from DILI(II-3)

18. The simplified scoring system (2008) of the IAIHGis a useful tool for every day clinical practice (II-2)By considering response to treatment, the revised scoring system (1999) of the IAIHG can be helpful indiagnosing difficult cases (II-2)

19. Adult patients with AIH and cholestatic lab changes should be considered for (MR) cholangiography torecognize sclerosing cholangtitis (II-3)

20. Co-existence of features of AIH and cholestatic liverdiseases can be observed, both at diagnosis and during follow-up.Diagnostic tests for PBC and PSCshould be performed in patients showing features of cholestasis (II-2)

Diagnosis AIH

Advanced fibrosis/ cirrhosis*

Active disease(HAI 4/18)

Mild disease (ALT 4/18) requires treatment. Treatment probably no longer indicatedin decompensated, burn-out cirrhosis, unless high inammatory score on liverbiopsy.



end-stage liver disease with liver failure and development of HCCis possible [181]. In addition, as AIH is a lifelong disease, and pro-gressive brosis may take many years to become clinically appar-ent, the observational studies published may have been too shortand may have included too few patients in order to demonstratethe benet of immunosuppressive therapy in milder disease. Theuctuating course of disease and the danger of subclinical diseaseprogression make it of critical importance, that if patients withmild disease are left untreated, they must nonetheless undergoa regular subsequent monitoring including follow-up liverbiopsy, if ALT and/or IgG levels increase or uctuate (Fig. 3). Insymptomatic patients and patients with advanced brosis or cir-rhosis, treatment should always be initiated as this represents anegative prognostic predictor [44,104,160,184]. In addition, evenin advanced brosis and cirrhosis substantial regression of scar-ring after successful treatment has been reported. In view ofthe progressive nature of AIH and the effectiveness of immuno-suppressive therapy, the consensus group recommends that allpatients with active disease should receive treatment.

21. Treatment of AIH should be aimed to obtain complete biochemical and histological resolution of the disease in order to prevent further progression of liver disease(II-2)

22. The management of patients with AIH should also include early recognition of extra-hepatic manifestations and symptoms, and associated autoimmune diseases as well as surveillance for disease specific, and treatment-associated complications (III)

23. All patients with active AIH should be treated (I) Dosage of therapy should be adapted to the activity of the disease (III)Only patients in (spontaneous) remission may not require therapy but must be closely followed (three-six monthly) (III)

Remission induction (Fig. 4)

The survival benet of corticosteroid therapy with or withoutazathioprine has been shown in a number of controlled trials per-formed in the 1960s and 1970s [175179]. In 1971, Cook et al.demonstrated survival benets of immunosuppressive therapycomparing prednisolone monotherapy (15 mg/day) with placebo.Mortality rates differed markedly (14% vs. 56%) [175]. The resultswere conrmed in a study from the Mayo Clinic one year later.This study compared prednisone monotherapy (starting with60 mg/day and reduced to 20 mg over four weeks), azathioprinemonotherapy (100 mg/day), combination therapy (prednisonestarting at 30 mg/day reducing to 10 mg/day maintenance com-bined with azathioprine at 50 mg/day) and placebo, [176] thebenecial effect on survival was similar with prednisonemonotherapy and prednisone/azathioprine combination therapy(mortality rate: 6% vs. 7% vs. 41% in the placebo group) [179].However, the combination regimen was associated with fewerside effects (10% vs. 44%) [185]. Histological remission wasachieved in 75% of patients after 18 months of active prednisonebased treatment but lagged behind clinical and biochemical

remission by several months. This trial further illustrated thatazathioprine monotherapy, used as induction therapy, resultedin a high mortality (36%). Murray-Lyon et al. also reported ahigher mortality rate of azathioprine monotherapy as inductiontherapy, compared to prednisone (24% vs. 5%) [177].

Comparing another strategy with titrated doses of pred-nisone (starting also at 60 mg/day) to maintain serum transam-inase activity at less than twice the upper limit of normal,Summerskill et al. showed that this led to less severe sideeffects compared with the xed dose regimen (starting with60 mg/day and reducing to 20 mg over four weeks) with com-parable effect on clinical symptoms and biochemical parame-ters. However, histological remission was achieved in only25% and 30% after 24 and 36 weeks respectively [186]. In1982 Tage-Jensen et al. demonstrated once more superiorityof prednisone monotherapy over azathioprine monotherapy ininducing remission [187].

Despite the limitations of these early studies (no testing forHCV available at that time), they provide compelling evidencethat the use of a prednis(ol)one/azathioprine combination regi-men has the best prole in combining high efcacy with minimalside effects. Although prednisolone monotherapy and pred-nisolone/azathioprine combination therapy is considered equallyeffective [34], frontline combination therapy with use of azathio-prine may be preferable, particularly in patients with a highanticipation of side effects such as in post-menopausal women,individuals with emotional instability, pre-existent osteoporosis,brittle diabetes, labile hypertension or obesity. Similarly, youngfemale patients are often concerned about weight gain and cos-metic side effects due to steroid treatment which might adverselyaffect adherence and outcome. A pragmatic approach to this issueis needed to ensure the best long-term outcomes. A proposeddosing regimen is shown in Table 7. Caution for the use of aza-thioprine is advisable in patients with malignancy, cytopeniaand established thiopurine methyltransferase (TPMT) deciency(see below) as well as pregnancy, and in these situations, arisk-benet analysis should be undertaken at an individualpatient level (see below).

Additional to the classical prednisolone/azathioprine regimenthat are also recommended in the AASLD [34] and BSG guidelines,[40] several slight modications have been proposed and arebeing used in clinical practice in many expert centres. A higherdose of predniso(lo)ne (up to 1 mg/kg/day) in combination withazathioprine was shown to result in a more rapid normalisationof serum transaminases in patients without cirrhosis [188].Although the absence of an early fall of transaminases[185,189] and failure to normalise [190192] are negative predic-tors of treatment success, this strategy seems promising. It needsto be conrmed that this translates into better long-term out-come and is really suitable for all patients.

Another reasonable strategy is to delay institution of azathio-prine and start with prednisone monotherapy. Delaying introduc-tion of azathioprine (usually by about two weeks) can bepragmatically helpful in managing patients with AIH, as it mayon the one hand help to resolve diagnostic uncertainties whileon the other hand avoids the diagnostic dilemma of discrimina-tion between azathioprine-induced hepatotoxicity from primarynon-response. Although hepatotoxicity of azathioprine is uncom-mon, its frequency is increased in patients with advanced liverdisease [3]. In general, treatment of AIH should be responseguided and treatment regimens should be individualised



according to the response of the patient and tolerance of treat-ment. A suggested induction strategy is shown in Fig. 4.

Therapy is aimed to obtain complete biochemical and histo-logical remission. In patients showing a prompt response withcomplete normalisation of transaminases and IgG within the nor-mal limits of a follow-up, liver biopsy to demonstrate also histo-logical remission is normally not required, as chances ofsignicant inammatory activity requiring increased immuno-suppression are very low. Follow-up biopsy is, like any invasiveprocedure, recommended, if a change of management is some-what likely to result from the procedure; this is particularly thecase in patients with sub-optimal response to immunosuppres-sion, and in patients with treatment side effects. In these cases,

individual risk assessment of disease progression needs to beweighed against (possible) treatment side effects, and assess-ment of disease grading can help in this. Ongoing studies suggestthat Fibroscan can also be used in follow-up. Increase in liverstiffness can be due to either disease reactivation with increasedinammatory inltrates and oedema, or due to progressive bro-sis (or both).

In a recent prospective, double blind, randomised, phase IIbtrial of patients without cirrhosis [193], budesonide (9 mg/day)and azathioprine (12 mg/kg/day) given for six months was com-pared to conventional prednisone and azathioprine-basedimmunosuppression. Budesonide/azathioprine was shown tonormalise transaminases more commonly and had fewer sideeffects compared to prednisone (40 mg/day tapered to10 mg/day) azathioprine (12 mg/kg/day) combination, and wassuperior in a combined endpoint. A complete biochemical remis-sion without steroid specic side effects was achieved in 47% ofpatients given budesonide vs. 18.4% given prednisolone.However, follow-up data on histology and long-term data arenot available. Remission rates in the control arm in this trial werevery low, and clearly lower than in earlier published case series,presumably due to xed dose reduction schedule in the pred-nisone group and a fairly low used prednisone dose. While budes-onide in this trial was given at a high dose until response wasobserved and treatment was response guided, the control armwas not, introducing a bias in the trial. Nonetheless, this trialhas demonstrated efcacy of budesonide in AIH. The successfuluse of budesonide in AIH has also been reported in other smallcase series [194196], but failure was also described in other ser-ies [197].

The decision to use budesonide in a particular patient shouldbalance the anticipated benecial side effect prole against

AIH

0.5-1 mg/kg/d predniso(lo)ne

Good response

Increase to

100 mg prednisolone i.v.

Response

Insufficient response

Consider non-compliance

yllaudargenirpoihtazaddAup to 1-2 mg/kg/d

Refer to specialist centre for confirmation of diagnosis, LTX-evaluation and/or alternative immunosuppressives

Manage alternative disease

Taper steroids (ideally trial of steroid withdrawal)

Individualize doses (consider checking 6-TG levels) to achieve and maintain normal ALT and IgG

Insufficient response

Azathioprin- intolerance

Second-line therapy (usually MMF)

Consider alternative diagnoses

Fig. 4. Therapeutic strategy in autoimmune hepatitis. Treatment requires induction of remission and prolonged maintenance therapy. Induction is delivered by steroidsand thiopurines are added as steroid sparing strategy. Laboratory endpoints are normalisation of IgG and ALT. MMF, mycophenolate mofetil.

Table 7. Treatment proposal for adult patients with AIH (e.g. 60 kg).

Week Prednisolone (mg/day) Azathioprine (mg/day)1 60

(= 1 mg/kg body weight)-

2 50 -3 40 504 30 505 25 100*

100*100*100*100*6 20

7 + 8 158 + 9 12.5From week 10 10

Reduction of prednisolone to 7.5 mg/day if aminotransferases reach normal levelsand after three-months to 5 mg/day, tapering out at three-four months intervalsdepending on patients risk factors and response. *Azathioprine dose of 12 mg/kgaccording to body weight.



uncertainties in strength and long-term efcacy. Budesonide hasa 90% rst pass hepatic clearance and should not be used in cir-rhotic patients, or those with peri-hepatic shunting, because ofthe high risk of side effects in patients not protected by effectiverst pass metabolism [198,199]. In addition, the decision shouldbe inuenced by the presence of concurrent extra-hepaticimmune-mediated diseases as exacerbations of these might bepossible [197,200]. Budesonide (9 mg/day) plus azathioprinemay therefore be considered in treatment-naive non-cirrhoticpatients with early stage disease and in whom untoward majorsteroid specic side effects are highly anticipated. However, wehave little information about the best approach to dose reductionin budesonide treatment. Due to the short half-life of budesonide,it is not clear if reduction to twice daily (6 mg) and to once daily(3 mg) dosing is reasonable, or if the thrice daily dosing should becontinued, reducing individual dose from 3 mg to 2 mg and 1 mg.

24. Predniso(lo)ne as initial therapy followed by the addition of azathioprine after two weeks is the first line treatment of AIH (I)

Initial dose of predniso(lo)ne should be between 0.5 and 1 mg/kg/day. Higher initial doses can induce remission more quickly albeit at the expense of steroid related side effects (II-2)

25. Azathioprine can be initiated whenever bilirubin levels are below 6 mg/dl (100 mol/L) and ideally two weeks after the initiation of steroid treatment. The initial dosage should be 50 mg/day, and increased depending on toxicity and response up until a maintenance dose of 1-2 mg/kg (II-2)

26. Treatment of AIH should be response guided and treatment regimens should be individualised (III)

A complete clinical, biochemical and histological remissionwith a sustained off-treatment response after treatment with-drawal is the most desirable treatment endpoint. However, thiscannot be reached in the majority of patients. In 80 to 90% ofpatients, transaminases promptly improve after institution ofimmunosuppressive treatment. In approximately 20% of patients,a sustained remission following withdrawal of immunosuppres-sive treatment can be achieved by nite treatment therapy (witha median follow-up of more than six years) [201], which might beimproved by the application of stringent endpoint criteria beforetreatment withdrawal (see below). Primary non-response toimmunosuppressive treatment is experienced in only a smallproportion of patients with AIH. Non-response (or very slowresponse) should therefore always lead to a careful reconsidera-tion of the diagnosis and/or re-evaluation of adherence to treat-ment. In particular, young, non-Caucasian patients with anacute or fulminant presentation and the nding of conuentnecrosis in liver tissue have a higher risk of treatment failure[20,202205]. Patients with liver failure and lack of improvementof serum bilirubin and MELD score during treatment should bereferred early to a transplant centre and LT should be consideredsince this disease phenotype has a high mortality without LT[42,202206]. In patients without liver failure and not respond-ing to initial treatment an increased dose regimen or alternativetreatment strategies can be applied (as discussed in detail insection Special patient populations) [207].

27. A failure of adequate response should lead to a reconsideration of diagnosis or re-evaluation of adherence to treatment (II-2)

28. In patients with sub-optimal response despite reconfirmation of diagnosis and adherence, dosage of prednisolone and azathioprine should be increased or alternative medications should be used (please see section on difficult to treat patients) (II-2)

29. Patients with acute severe AIH should be treated with high doses of intravenous corticosteroids (1 mg/kg) as early as possible. Lack of improvement within seven days should lead to listing for emergency liver transplantation (III)

Treatment withdrawal (Fig. 5)

The majority of AIH patients respond well to steroid basedimmunosuppressive treatment and serum transaminasesimprove to levels within the normal range [190,208210].Complete normalisation of transaminases as well as normalisa-tion of IgG levels should be the aim of treatment in patients withautoimmune hepatitis as persisting elevations of transaminasesare predictive of; (i) a relapse after treatment withdrawal;(ii) activity on liver biopsy; (iii) progression to cirrhosis; and(iv) poor outcome [185,190192,208,211,212].

Histological resolution of disease typically lags behind afterreaching the biochemical endpoint [176]. There is no clear evi-dence of optimal treatment duration. However, treatment shouldbe continued long enough to reach histological remission asresidual interface hepatitis is still found in patients with nor-malised ALT levels and is predictive of disease relapse [212].Together with normalised serum transaminases normalisationof serum IgG appears to also be predictive of histological resolu-tion [108].

Treatment should be continued for at least three years and forat least 24 months after complete normalisation of serumtransaminases and IgG levels (biochemical remission). Longertreatments may decrease the frequency of relapse and may there-fore be considered. For patients with severe initial presentationand low tolerance of induction treatment, performance of a liverbiopsy prior to treatment withdrawal is advisable as histologicalndings are predictive of brosis progression and relapse [108].In patients with continued histological disease activity (HAI >3),immunosuppressive treatment should not be discontinued, asrelapse is almost certain to occur. A recent paper showed thatALT levels below half the upper limit of normal together withIgG levels below 12 g/L were highly predictive for successfultreatment withdrawal [213]. A trial of treatment withdrawalshould be undertaken by stepwi

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